1. Field of the Invention
The present invention relates to a new industrial process for the preparation of D camphorate of L carnitinamide and D camphorate of D carnitinamide.
2. Description of the Prior Art
As known, for instance from the Belgian Pat. No. 660039, the D camphorates of L and D carnitinamide are key intermediates in the preparation of useful therapeutic agents. For instance, the D Camphorate of L carnitinamide can be converted to L-carnitinamide which exhibits remarkable stimulating respiratory activity. Moreover, L-carnitinamide as well as D carnitinamide can be used for the industrial production of laevorotatory and dextrorotatory carnitine hydrochloride respectively, which are also known, useful therapeutic agents.
The previously proposed processes for the production of laevorotatory and dextrorotatory carnitine hydrochloride may be divided into two groups; processes that use the hydrochloride of DL Carnitine nitrile as the starting compound, and a process using the hydrochloride of DL Carnitinamide as the starting compound.
The first group, namely, processes using the hydrochloride of D, L carnitine nitrile are chronologically those proposed by E. STRACK et al. (Z. Physiol. Chem. 318, 129, 1960), HORIUCHI et al. (TOKIO KOHO SHO 40-3891), AYATA (YAKUGAKU ZASSHI 81, 778, 1961) and T. DOHI et al. (Japan Pat. No. 63291/1965 of the OTSUKA Pharmaceutical Co.).
In general, it has been demonostrated that these methods are not economically feasible for the industrial production of L carnitine chloride since some of them are based upon a double formation of salts in order to achieve the separation of the laevorotatory isomer (method proposed by E. STRACK and method proposed by AYATA), while the other two methods comprise the use of particularly expensive acids, such as L-camphorsulfonic acid (HORIUCHI et al.) and D acetylglutamic acid (T. DOHI et al.).
Moreover, the use of the nitrile of carnitine is not advisable for this type of resolution since the method for preparing the nitrile involves the attainment of a compound with a high number of salt impurities (10-15%) which are not easily separable; such impurities considerably complicate the resolution process of the two optical antipodes.
Furthermore, in the successive hydrolysis of the optically active carnitine nitrile to Carnitinamide and thence to carnitine, racemization phenomena may occur. This untoward effect takes place especially in the conversion to carnitinamide and, therefore, the final compound that is obtained does not have the desired optical purity.
The second group of processes which use racemic carnitinamide as the starting compound has the advantage of utilizing an easily available compound, which has a high degree of purity and is easily hydrolyzable to carnitine without danger of racemization.
The process using carnitinamide hydrochloride as the starting compound for resolution is disclosed in the above-mentioned Belgian Pat. No. 660039. Such a process comprises the use of D camphoric acid, which is also easily available at a low price, for producing the D camphorate of D,L carnitinamide.
However, this process presents a serious drawback and, consequently, finds little industrial application since, in order to form the D camphorate of D,L carinitinamide, it is first necessary to form the ammonium salt of D camphoric acid with ammonia; the ammonium D camphorate that is formed is then converted to silver D Camphorate by the action of silver nitrate. Since the carnitinamide is in the hydrochloride salt form, the formation of this silver salt is essential in order to eliminate the chloride ion. Such a process is, therefore, very expensive (because of the imperative use of the silver compound) and difficult to carry out industrially in that the various steps of the process have to be carried out away from the light in order to avoid marked blackening of the reaction vessels, due to the large quantity of AgCl which is formed. The final compound may in addition be rendered impure by the presence of silver ions.